What Causes Parkinson’s Disease?

What Causes Parkinson’s Disease? Understanding the Complex Origins of a Growing Pandemic

Parkinson’s disease (PD) affects over 10 million people worldwide, making it the second most common neurodegenerative disorder after Alzheimer’s disease. Yet despite decades of research, the question “What causes Parkinson’s disease?” doesn’t have a simple answer. The reality is far more complex than researchers once believed.

The Parkinson’s Pandemic: A Growing Crisis

Between 1990 and 2016, the global prevalence of Parkinson’s disease increased by approximately 74% in raw numbers, with age-adjusted prevalence rising by 22%. This dramatic increase has led some experts to describe the situation as a “Parkinson’s pandemic.” While our aging population explains part of this trend, other factors are clearly at play, including declining mortality from cardiovascular disease, increased industrialisation, and reduced smoking rates.

Understanding what triggers this debilitating condition has never been more urgent.

Beyond Genetics: A Multifactorial Disease

For years, scientists searched for a single cause of Parkinson’s disease. Today, we know the answer is far more nuanced. PD is a multifactorial disease resulting from complex interactions between genetic predisposition and environmental factors.

The Genetic Component

Seven genes are currently designated as monogenic causes of Parkinson’s disease, including LRRK2, SNCA, PARKIN, and PINK1. However, studies of twins with lifelong follow-up estimated the heritability of Parkinson’s disease to be only 30%, supporting a larger role for environmental and behavioural factors.

This means that even if you carry genetic risk variants, whether you develop Parkinson’s depends heavily on environmental exposures and lifestyle factors throughout your life.

Environmental Triggers: The Hidden Culprits

Some of the strongest evidence for Parkinson’s disease causation points to environmental toxins, particularly those encountered through our nose and digestive system.

Pesticides and Agricultural Chemicals

Pesticides associated with Parkinson’s disease have biochemical effects including mitochondrial dysfunction, inflammation, and alterations of the microbiome that are thought to be important to Parkinson’s disease.

Farmers and farmworkers exposed to pesticides show higher rates of olfactory impairment years after exposure, and occupational pesticide use is associated with increased odds of reporting poor sense of smell. This is particularly significant because loss of smell often precedes motor symptoms by years or even decades.

Air Pollution and Industrial Toxins

Chlorinated solvents (used widely for industrial cleaning) are associated with increased risk of Parkinson’s disease in humans and cause parkinsonism-associated toxicity in animal models. Exposure to air pollution, welding fumes, and certain metals has also been implicated, though evidence remains inconsistent across studies.

The Gut: A Revolutionary Perspective

Perhaps the most exciting area of Parkinson’s research focuses on an unexpected organ: the gut. This represents a paradigm shift in how we understand neurodegenerative disease.

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The Body-First Hypothesis

The Braak hypothesis posits that PD pathogenesis may first initiate in the olfactory structures and the gut enteric nerves, years if not decades before spreading to the substantia nigra where dopaminergic neuron death occurs. This “body-first” model suggests that for many patients, Parkinson’s doesn’t start in the brain at all.

Supporting this theory, the percentage of undiagnosed screen-detected cases of parkinsonism increases from 18% in people aged 65-70 years to over 50% in those older than 85 years, and many of these individuals show gastrointestinal symptoms years before motor problems appear.

Gastrointestinal Symptoms as Early Warning Signs

Constipation strongly predicts future risk of Parkinson’s disease with up to 10 years of follow-up. In fact, in a reconstructed timeline based on data from idiopathic REM sleep behaviour disorder patients, poor olfaction appeared to be the first symptom starting more than 20 years before phenotypical conversion to PD or Lewy body dementia, with constipation beginning approximately 10 years before conversion.

The Small Intestine: Ground Zero for Pathology

Recent research has zeroed in on the small intestine as a critical site where Parkinson’s pathology may begin. Up to 54% of Parkinson’s patients show small intestinal bacterial overgrowth (SIBO), which is associated not only with gastrointestinal symptoms but also with more severe motor fluctuations.

In Parkinson’s disease, abnormal protein clumps (called α-synuclein) appear more often in the upper digestive system than the lower digestive system. Studies found these clumps in 83.6% of upper gut samples (like the duodenum and small intestine) compared to 64.3% in the lower gut.

Even more striking, preclinical evidence supports the body-first model, showing that fecal transplants from PD patients into mice can induce small intestinal dysbiosis, local inflammation, increased intestinal permeability, and ultimately neuroinflammation and abnormal protein clump accumulation.

The Microbiome Connection: An Ecosystem in Crisis

The gut houses trillions of microorganisms—bacteria, viruses, and fungi—that play crucial roles in our health. In Parkinson’s disease, this microbial community becomes severely disrupted.

Dysbiosis in Parkinson’s Patients

Studies consistently document an increase in opportunistic genera such as Akkermansia and a reduction in short-chain fatty acid (SCFA)-producing bacteria including Lachnospiraceae and Faecalibacterium in Parkinson’s patients. This microbial profile suggests a pro-inflammatory state with a rise in mucin-degrading taxa and loss of beneficial strains.

Gut microbiota in Parkinson’s disease is characterised by increased levels of pro-inflammatory Proteobacteria (such as Ralstonia) in duodenal biopsies, with accumulation of oligomeric α-synuclein in the mucosa correlating positively with Ralstonia abundance.

How Microbes May Trigger Disease

Bacterial amyloid proteins such as curli from E. coli can increase α-synuclein aggregation in both the gut and brain through cross-seeding mechanisms, leading to more severe motor deficits and gastrointestinal dysfunction in mouse models.

Germ-free mice or mice treated with antibiotics to eradicate their microbiota show little synucleinopathy, neuroinflammation, and motor symptoms, while introducing Parkinson’s patient microbiota to these mice results in PD pathology and motor impairment.

This suggests that specific bacterial strains in the gut may actively promote the protein misfolding and aggregation that characterises Parkinson’s disease.

The Dual-Hit Hypothesis: Two Routes to the Brain

The dual-hit hypothesis proposes that environmental toxins such as pesticides, air pollutants, metals, or viruses may enter the body via the nasal cavity or the gut, initiate PD pathogenesis, gain access to the brain via the olfactory pathway or the vagus nerve, and eventually lead to clinical PD.

These are the only two anatomic sites where human mucosal surfaces directly interact with the environment while also having established pathways to the brain. This explains why both olfactory impairment and constipation are among the most robust prodromal symptoms, potentially appearing decades before motor dysfunction.

Protective Factors: The Paradoxes

Interestingly, some factors appear to reduce Parkinson’s risk, though the mechanisms remain debated:

The Smoking Paradox

The association between cigarette smoking and reduced Parkinson’s disease risk is arguably the best-established epidemiological observation for PD, with genetic variants that determine smoking liability associated with lower risk of Parkinson’s disease in Mendelian randomisation studies.

However, current smokers are about 2-3 times more likely to develop poor olfaction, and smoking is associated with a higher risk of REM sleep behaviour disorder, both prodromal Parkinson’s symptoms. This contradiction remains unresolved.

Coffee, Exercise, and Diet

Coffee and tea drinking are associated with lower risk of Parkinson’s disease, particularly in men, while physical activity and exercise are associated with lower risk in a dose-response manner. Just make sure your coffee has been tested to be mycotoxin free.

Diets high in vegetables, fruits, and grains are associated with reduced risk, while dietary dairy intake is associated with greater risk of Parkinson’s disease.

Inflammation: The Common Thread

A pattern emerges when examining all these risk factors: inflammation. Anti-inflammatory drug use is associated with a decrease in risk of Parkinson’s disease, and chronic intestinal inflammation and increased gut permeability are strongly related to neurodegenerative processes in PD.

Inflammaging—low-grade systemic inflammation in the elderly—may explain why many diseases typical of aging share an inflammatory pathogenesis, with altered balance between beneficial and pro-inflammatory bacteria observed in aged mice and believed associated with enteric nervous system degeneration.

The Prodromal Period: Decades in the Making

Perhaps the most important insight from recent research is that Parkinson’s disease develops over an extraordinarily long time period. By the time of PD diagnosis with cardinal motor signs, the disease might have undergone decades of prodromal development, during which many factors may come into play to initiate pathology or modify its progression.

This extended timeline includes:

• 20+ years before diagnosis: Loss of smell begins.
• 10 years before diagnosis: Constipation develops.
• 5 years before diagnosis: Motor signs emerge.
• At diagnosis: Approximately 70% of dopaminergic neurons already lost.

Implications for Prevention and Treatment

Understanding these causes opens new avenues for intervention:

Primary Prevention

Multi-pronged prevention strategies are required that tackle population-based primary prevention, including banning neurotoxic agents and promoting physical activity. Applying a population approach to increase moderate to vigorous physical activity could prevent 14.5% of all current cases.

Targeting the Gut

Probiotics, prebiotics, and dietary modifications show promise for improving both motor and non-motor symptoms in Parkinson’s patients, with specific strains like Bifidobacterium breve and Lactobacillus plantarum demonstrating neuroprotective effects in preclinical studies.

A four-week high-fiber diet supplemented with the prebiotic lactulose resulted in increased Bifidobacteria, elevated fecal short-chain fatty acid production, improvements in constipation, and elevated neuroprotective metabolites.

My go to supplements to support a higher fibre intake are PHGG and Psyllium husk. The PHGG can be easily added to your morning coffee or tea, and psyllium husk can simply be taken in water. I often add it to porridge or muesli also.

Medication Interactions

The gut microbiome even affects how Parkinson’s medications work. Some gut bacteria express enzymes that convert levodopa to dopamine before it reaches the brain, reducing medication effectiveness. Moderate responders to L-DOPA exhibit higher abundance of the bacterial tyrosine decarboxylase gene and Enterococcus faecalis compared to good responders.

The Future: From Understanding to Action

Future international collaborations will be required to triangulate evidence from basic, applied, and epidemiological research, thereby enhancing the understanding and prevention of Parkinson’s disease at a global level.

The gut microbiome is increasingly recognised as a potential biomarker for Parkinson’s disease, with reliable microbiota signatures potentially improving clinical diagnosis even in the premotor phase.

Conclusion: A New Paradigm

The causes of Parkinson’s disease are complex and multifaceted, involving an intricate dance between our genes, the toxins we encounter, the bacteria in our gut, and the lifestyle choices we make throughout our lives. The emerging picture suggests that for many patients, Parkinson’s begins not in the brain but in the gut, triggered by environmental exposures that alter the microbiome and initiate a cascade of inflammation and protein mis-folding that eventually reaches the brain decades later.

This new understanding offers hope. By identifying at-risk individuals early through olfactory testing, gut microbiome analysis, and other biomarkers, and by intervening with dietary changes, probiotics, toxin avoidance, and lifestyle modifications, we may be able to prevent or delay this devastating disease.

The gut-brain axis isn’t just an interesting research topic—it’s a fundamental element of Parkinson’s pathogenesis, offering unprecedented opportunities for prevention and treatment. As research continues to unravel these connections, we move closer to a future where Parkinson’s disease can be stopped before it starts.

References

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